Description: FIELD OF THE INVENTION

Present invention provides a process for the preparation of Haloperidol of Formula I, its intermediates, salt and purification thereof,

Formula I.

BACKGROUND OF THE INVENTION

Haloperidol, chemical name is 4-[4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl]-1-(4-fluorophenyl)butan-1-one and is represented by the Formula I. It is also used in the form of decanoate salt known as Haloperidol decanoate, chemically known as [4-(4-chlorophenyl)-1-[4-(4-fluorophenyl)-4-oxobutyl]piperidin-4-yl] decanoate and is represented by Formula II. The Haloperidol and its decanoate salt is marketed as Haldol.
,
Formula I Formula II

Haloperidol is a conventional high potency first generation (typical) antipsychotic agent indicated for the treatment of schizophrenia, tics in Tourette syndrome, mania in bipolar disorder, delirium, agitation, acute psychosis, and hallucinations in alcohol withdrawal. Haloperidol competitively blocks postsynaptic dopamine (D2) receptors in the mesolimbic system of the brain, thereby eliminating dopamine neurotransmission and leading to antidelusionary and antihallucinagenic effects.

Haloperidol was first time disclosed in US3438991 A and its decanoate salt was disclosed in US3408356 A.

PL140006 B1 discloses process for the preparation of Haloperidol intermediate i.e. 4-hydroxy-4-(4-chlorophenyl)piperidine by treating 4-piperidone with 1-bromo-4-chloro benzene by Grignard reaction using Magnesium turnings in tetrahydrofuran and toluene. PL’006 discloses that the above said compound is isolated in pure form by using the methods such as extractions and crystallizations.

CN103145607 A discloses preparation of Boc-protected 4-hydroxy-4-(4-chlorophenyl)piperidine by reacting N-tert-butoxycarbonyl-4-piperidone with chloro phenyl magnesium bromide in presence of THF followed by workup to give Boc-protected 4-hydroxy-4-(4-chlorophenyl)piperidine

4-hydroxy-4-(4-halophenyl)piperidine compounds such as 4-monosubstituted phenyl-1,2,3,6-tetrahydropyridine hydrochloride used for the preparation of Haloperidol. The process involves preparation of Boc-protected 4-hydroxy-4-(4-halophenyl)piperidine through Grignard reaction followed by de-protection in hydrochloric acid.

From above disclosures, it can be seen that there are few processes known from the prior published references for the preparation of 4-hydroxy-4-(4-chlorophenyl)piperidine intermediate of Haloperidol. The preparation of advanced intermediate i.e. 4-hydroxy-4-(4-chlorophenyl)piperidine or its acid addition salt, is an important reaction step of Haloperidol process and the present invention is focussed towards the preparation and purification of the advanced intermediate, wherein said process is simple and economically favourable.

OBJECT OF THE INVENTION
The main object of the present invention is to provide an improved process for the preparation of advanced intermediate of Haloperidol i.e. 4-hydroxy-4-(4-chlorophenyl)piperidine of Formula III or its acid addition salt.

Another object of the present invention is to provide process of preparing Haloperidol and pharmaceutically acceptable salt thereof, by employing the use of advanced intermediate, 4-hydroxy-4-(4-chlorophenyl)piperidine of Formula III or its acid addition salt.

Another object of the present invention is to provide a process of purification of Haloperidol and pharmaceutically acceptable salt thereof.

SUMMARY OF THE INVENTION
The present invention relates to an improved process for the preparation of advanced intermediate i.e. 4-hydroxy-4-(4-chlorophenyl)piperidine of Formula III or its acid addition salt; and use of said intermediate in the preparation of Haloperidol and its pharmaceutically acceptable salts thereof.

Accordingly, in one aspect, the present invention provides a process for the preparation of Haloperidol or its pharmaceutically acceptable salt, wherein said process comprising the steps of:
a) converting compound of Formula IV to compound of Formula VI in presence of chloro bromo benzene of Formula V, magnesium source and haloalkane,
;
b) converting compound of Formula VI to 4-hydroxy-4-(4-chlorophenyl)piperidine of Formula III in presence of suitable base;
; and
c) optionally converting compound of Formula III to its corresponding pharmaceutically acceptable salt;
d) converting compound of Formula III or its acid addition salt to Haloperidol or its pharmaceutically acceptable salt.

In another aspect, the present invention provides a process for the preparation of Haloperidol or its pharmaceutically acceptable salt, wherein said process comprising the steps of:
a) converting compound of Formula IV to compound of Formula VI in presence of chloro bromo benzene of Formula V, magnesium source, dibromoethane, and suitable solvent,
;
b) converting compound of Formula VI to 4-hydroxy-4-(4-chlorophenyl) piperidine of Formula III in presence of sodium hydroxide and suitable solvent,
;
c) purifying compound of Formula III in suitable solvent; and
d) converting compound of Formula III or its acid addition salt to Haloperidol or its pharmaceutically acceptable salt.

In another aspect, the present invention provides stable crystalline form of Haloperidol, wherein said crystalline form is stable after exposure to 40°C/75% RH for a period of six months or 25°C/60% RH, for a period of at least 12 months and contains less than about 0.5% (wt/wt) total impurities.

In another aspect, the present invention provides a process for the preparation of crystalline form of Haloperidol, comprising the steps of;
a) providing a solution of Haloperidol in ester solvent;
b) heating to solution between 65oC -90oC;
c) isolating solid mass and optionally treating with one or more suitable solvent; and
b) isolating crystalline Haloperidol.

In another aspect, the present invention provides a process for the preparation of crystalline form of Haloperidol, comprising the steps of;
a) providing a solution of Haloperidol in ethyl acetate;
b) heating to solution between 65oC -90oC;
c) isolating solid mass and treating with mixture of acetone and methanol at ambient temperature;
d) isolating solid mass and dissolving in ethyl acetate at 65oC -90oC; and
b) cooling and isolating crystalline Haloperidol.

In another aspect, the present invention provides stable crystalline form of Haloperidol, wherein said crystalline form is characterized by X-Ray powder diffraction pattern comprising peaks at about 6.5, and 19.5±0.2o?.

In yet another aspect, the present invention provides stable crystalline form of Haloperidol, wherein said crystalline form is characterized by DSC having endotherm peak at 154.01oC and moisture content of less than about 1.0% w/w characterized by TGA.

In another aspect, the present invention provides stable crystalline form of Haloperidol, wherein said crystalline form is characterized by X-Ray powder diffraction pattern comprising peaks at about 6.5, 13.0, 14.9, 19.5, 19.8, 26.1, 31.7, and 36.2 ± 0.2o2?.

In another aspect, the present invention provides stable crystalline form of Haloperidol decanoate, wherein said crystalline form is characterized by X-Ray powder diffraction pattern comprising peaks at about 5.1, 21.7 and 23.5 ±0.2o?.

In another aspect, the present invention provides stable crystalline form of Haloperidol decanoate, wherein said crystalline form is characterized by DSC having endotherm peaks at 44.5 oC and 245.1 oC and moisture content of less than about 1.0% w/w characterized by TGA.

Brief Description of Drawings:
Figure 1 is X-Ray powder diffractogram (PXRD) of Haloperidol Free base.
Figure 2 is DSC of Haloperidol Free base.
Figure 3 is TGA of Haloperidol Free base.
Figure 4 is X-Ray powder diffractogram (PXRD) of Haloperidol decanoate.
Figure 5 is DSC of Haloperidol decanoate.
Figure 6 is TGA of Haloperidol decanoate.

DETAILED DESCRIPTION OF THE INVENTION

Definitions:

The term “suitable solvent” as used in the context of the present invention is one or more solvent mixture selected from protic and aprotic solvents such as group comprising of, but not limited to, alcohols such as methanol, ethanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, hexafluoroisopropyl alcohol, ethylene glycol, 1-propanol, 2-propanol (isopropyl alcohol), 2-methoxyethanol, 1-butanol, 2-butanol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, polyethylene glycol, 1-, 2-, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, phenol, glycerol; halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, trichloroethylene, perchloroethylene, 1,1,1-trichloroethane, 1,1,2-trichloroethane, chloroform, carbon tetrachloride; ethers such as diethyl ether, diisopropyl ether, methyl t-butyl ether, glyme, diglyme, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, dibutyl ether, dimethylfuran, 2-methoxyethanol, 2-ethoxyethanol, anisole; ketone solvents such as acetone, ethyl methyl ketone, diethyl ketone, methyl isobutyl ketone; esters solvents such as ethyl acetate, n-propyl acetate, n-butyl acetate, iso propyl acetate, isobutyl acetate, t-butyl acetate, ethyl formate, methyl acetate, methyl propanoate, ethyl propanoate, methyl butanoate, ethyl butanoate; hydrocarbon such as toluene, xylene, hexane, heptane, n-pentane, anisole, ethyl benzene, cyclohexane and the like; nitriles such as acetonitrile, propionitrile, butanenitrile; water; and mixtures thereof.

The term “Magnesium source” as used in the context of the present invention is magnesium metal in the form magnesium ribbon or magnesium turning.

The present invention will now be explained in details. While the invention is susceptible to various modifications and alternative forms, specific embodiment thereof will be described in detail below. It should be understood, however that it is not intended to limit the invention to the particular forms disclosed, but on the contrary, the invention is to cover all modifications, equivalents, and alternative falling within the scope of the invention as defined by the appended claims.

The steps of a method may be providing more details that are pertinent to understanding the embodiments of the present invention and so as not to obscure the disclosure with details that will be readily apparent to those of ordinary skill in the art having benefit of the description herein.

Further characteristics and advantages of the process according to the invention will result from the description herein below of preferred exemplary embodiments, which are given as indicative and non-limiting examples.

Accordingly, in one embodiment, the present invention provides a process for the preparation of Haloperidol or its pharmaceutically acceptable salt, wherein said process comprising the steps of:
a) converting compound of Formula IV to compound of Formula VI in presence of chloro bromo benzene of Formula V, magnesium source and haloalkane,
;
b) converting compound of Formula VI to 4-hydroxy-4-(4-chlorophenyl)piperidine of Formula III in presence of suitable base;
; and
c) converting compound of Formula III to Haloperidol or its pharmaceutically acceptable salt.

In another embodiment, the haloalkanes used in preparation of compound of Formula VI is selected from, but not limited to, dibromoethane, 1-bromo-2-chloroethane, 1-bromo-3-chloro propane, bromoethane and the like.

In another embodiment, the suitable base used for de-protecting compound of Formula VI is selected from, but not limited to, sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium carbonate, cesium carbonate, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, calcium hydroxide, and the like.

In another embodiment, the present invention provides a process for the preparation of Haloperidol or its pharmaceutically acceptable salt, wherein said process comprising the steps of:
a) converting compound of Formula IV to compound of Formula VI in presence of chloro bromo benzene of Formula V, dibromoethane, and suitable solvent,
;
b) converting compound of Formula VI to 4-hydroxy-4-(4-chlorophenyl)piperidine of Formula III in presence of sodium hydroxide and suitable solvent,
;
c) purifying compound of Formula III in suitable solvent; and
d) converting compound of Formula III or its acid addition salt to Haloperidol or its pharmaceutically acceptable salt.

In another embodiment, the present invention provides stable crystalline form of Haloperidol, wherein said crystalline form is stable after exposure to 40°C/75% RH for a period of six months or 25°C/60% RH, for a period of at least 12 months and contains less than about 0.5% (wt/wt) total impurities.

In another embodiment, the present invention provides a process for the preparation of crystalline form of Haloperidol, comprising the steps of;
a) providing a solution of Haloperidol in ester solvent;
b) heating to solution between 65 oC-90oC;
c) isolating solid mass and optionally treating with one or more suitable solvent; and
b) isolating crystalline Haloperidol.

In another embodiment, the ester solvent used for crystallization of haloperidol is selected from, but not limited to, ethyl acetate, propyl acetate, butyl acetate, propene acetate and mixture thereof.

In another embodiment, the present invention provides a process for the preparation of crystalline form of Haloperidol, comprising the steps of;
a) providing a solution of Haloperidol in ethyl acetate;
b) heating to solution between 65 oC-90oC;
c) isolating solid mass and treating with mixture of acetone and methanol at ambient temperature;
d) isolating solid mass and dissolving in ethyl acetate at 65 oC-90oC; and
e) cooling and isolating crystalline Haloperidol.

In another embodiment, the present invention provides stable crystalline form of Haloperidol, wherein said crystalline form is characterized by X-Ray powder diffraction pattern comprising peaks at about 6.5 and 19.5±0.2o?.

In another embodiment, the present invention provides stable crystalline form of Haloperidol, wherein said crystalline form is characterized by X-Ray powder diffraction pattern comprising peaks at about 6.5, 13.0, 14.9, 19.5, 19.8, 24.6, 26.1, 31.7, and 36.2 ± 0.2o2?.

In another embodiment, the present invention provides stable crystalline form of Haloperidol, wherein said crystalline form is characterized by DSC having endotherm peak at 154.01oC and moisture content of less than about 1.0% w/w characterized by TGA.

In another aspect, the present invention provides stable crystalline form of Haloperidol decanoate, wherein said crystalline form is characterized by X-Ray powder diffraction pattern comprising peaks at about 5.1, 21.7 and 23.5 ±0.2o?.

In another embodiment, the present invention provides stable crystalline form of Haloperidol decanoate, wherein said crystalline form is characterized by DSC having endotherm peaks at 44.5 oC and 245.1 oC and moisture content of less than about 1.0% w/w characterized by TGA.

In another embodiment, the intermediate of Formula III is isolated by methods known in the art or any procedure disclosed in the present invention wherein said method is selected from, but not limited to, filtration, distillation, solvent evaporation under atmospheric pressure or reduced pressure / vacuum such as a rotational distillation using Büchi® Rotavapor®, spray drying, freeze drying, thin film drying, agitated thin film drying, rotary vacuum paddle dryer (RVPD), lyophilisation and the like.

Moreover, drying at any stage of the process may be carried out in a tray dryer, vacuum oven, air oven, cone vacuum dryer, rotary vacuum dryer, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying may be carried out at temperatures less than about 100°C, less than about 80°C, less than about 60°C, less than about 50°C, less than about 30°C, or any other suitable temperatures, at atmospheric pressure or under a reduced pressure. The drying may be carried out for any desired times until the required product quality is achieved. The dried product may optionally be subjected to a size reduction procedure to produce desired particle sizes. Milling or micronization may be performed before drying, or after the completion of drying of the product. Techniques that may be used for particle size reduction include, without limitation, ball, roller or hammer milling; or jet milling; or bead milling.

In another embodiment, the Haloperidol or its pharmaceutically acceptable salt is isolated by method selected from lyophilisation, filtration, evaporation under vacuum, centrifugation, or by any of the known conventional methods.

In further embodiment, the Haloperidol and its pharmaceutically acceptable salt as obtained by the process of the present invention is characterized by purity of about 99.5% and above.

The present invention is explained below by way of examples. However, the examples are provided as one of the possible way to practice the invention and should not be considered as limitation of the scope of the invention.

EXAMPLES

EXAMPLE 1: Synthesis of 4-Chloro-1-(4-fluorophenyl)butan-1-one
Charged dichloromethane (2500.0 ml) and aluminium chloride (832.50 g) and cooled the reaction mass to 0±5°C. Added 4-chlorobutyryl chloride (806.97 g) slowly within 2-3 hour into the above reaction mass at 0 to 5°C. Stirred the mass for 1 hour at 0 to 5°C. Added Fluorobenzene (500.0 g) slowly within 2-3 hour to the reaction mass at 0 to 5ºC. Raised the reaction mass temperature gradually to 20-25ºC. Stirred the mass for 4 hours at 20-25ºC till completion of reaction. Quenched the reaction mass in ice cold DM water (2500.0 ml) at 0-20ºC and stirred the reaction mass for 30 minutes at 10-20ºC. Added concentrated hydrochloric acid (1000.0 ml) in the above reaction mass within 10-15 minutes at 10-20ºC. Stirred the reaction mass for 30 minutes at 10-20ºC. Separated the layers and washed the organic layer with 5% (w/v) sodium bicarbonate solution. Separated the layers and distilled out the organic layer atmospherically at 35-65ºC and degassed it under vacuum. Distilled out the crude mass under vacuum (15 to 6 mbar) at 140-165ºC to get 986.0 g of desired compound.

EXAMPLE 2: Synthesis of Ethyl 4-(4-chlorophenyl)-4-hydroxypiperidne-1-carboxylate
Charged magnesium turning (32.40 g) into 5 litre 4 neck round bottom flask in water bath at 20-25ºC and heated the mass at 45-50ºC and maintained for 60-90 minutes. Meanwhile prepared 1-bromo-4-chloro benzene solution [1-bromo-4-chloro benzene (250.0 g) dissolves in Tetrahydrofuran (250.0 ml)] in another round bottom flask. Charged tetrahydrofuran (250.0 ml) and 1,2-dibromoethane (1.0 g) in the above 5 litre 4 neck round bottom flask and added 1-bromo-4-chloro benzene solution slowly in 3-4 hrs at 40-66ºC. Stirred the reaction mass for 60-90 minute at 40-60ºC. Cooled the reaction mass at 25-40°C. Meanwhile prepared N-carbethoxy-4-piperidone solution [N-carbethoxy-4-piperidone (201.18 g) dissolved in tetrahydrofuran (500.0 ml)] in another round bottom flask and slowly added to the reaction mass within 3-4 hrs at 25-40ºC. Stirred the reaction mass for 60-90 minute at 25-40ºC. After completion of reaction, distilled out tetrahydrofuran under vacuum at 45-50ºC. Cooled the reaction mass to 20-25ºC. Charged DM water (500.0 ml) to the above reaction mass and stirred it for 60-90 minute till material is dissolved in water. Cooled the reaction mass to 25-30ºC. Adjusted the pH of the reaction mass to 4-6 with sulphuric acid solution [Conc. Sulphuric acid (30.0 ml) dissolve in DM water (500.0 ml)] at 25-30ºC]. After pH adjustment, stirred the reaction mass for 15-30 minute at 25-30ºC. Charged ethyl acetate (1000.0 ml) in to the above reaction mass and stirred it for 15-20 minute. Filtered the reaction mass through hyflo bed and washed with ethyl acetate (50.0 ml). After filtration, separated the layers. Extracted the aqueous layer with ethyl acetate (125.0 ml) at 25-30ºC. Separated the layers. Combined both organic layer and washed with 5% sodium bicarbonate solution. Separated the layers. Distilled out organic layer under vacuum at 45-55ºC till residue remains. Crystallised the residue with diisopropylether to get desired compound.

EXAMPLE 2a: Synthesis of Ethyl 4-(4-chlorophenyl)-4-hydroxypiperidne-1- carboxylate
Charged magnesium turning (16.1 g) and tetrahydrofuran (125 ml) and 1,2-dibromoethane (0.5 g) in RBF. Solution of 1-bromo-4-chloro benzene solution (124.26 g) dissolved in Tetrahydrofuran (125.0 ml)] slowly added at 35-45ºC and stirred for 5 minutes. N-carbethoxy-4-piperidone (100.0 g) dissolved in Toluene (400 ml)] slowly added at 35-45ºC and stirred. After completion of reaction, quench reaction mass with water and acidify (pH4-6) with sulphuric acid solution. Charged toluene and filtered the reaction mass. Extracted the material with toluene and washed organic layer with NaHCO3 solution and NaCl solution. Concentrated the organic layer to get crude material. Crude obtained is purified in mixture of Toluene and di-isopropyl ether. Cooled the mass and filtered to give wet cake. Proceed wet cake as such for next step. Wet cake weight: 110g.

EXAMPLE 3: Synthesis of 4-(4-Chlorophenyl)-4-hydroxypiperidine:
Charged methanol (1200.0 ml) and ethyl 4-(4-chlorophenyl)-4-hydroxypiperidne-1-carboxylate (240.0g) in a 3 litre four neck round bottom flask at 20-25ºC. Stirred the reaction mass at 20-25ºC. Meanwhile prepared sodium hydroxide solution [sodium hydroxide (338.93 g) dissolve in DM Water (480.0 ml)] & cooled to 20-25°C. Added the sodium hydroxide solution into the above round bottom flask in 2-3 hours at 20-50°C. Heated the reaction mass to 75-80°C. Stirred the mass till reaction completion at 75-80°C. After reaction complies, distil out methanol under vacuum (150-200 mbar) at 45-50°C. Cooled the reaction mass to 20-30°C. Added DM Water (480.0 ml) and stirred the mass for 90-120 minutes at 20-30°C. Filtered the mass & washed with DM Water (120.0 ml) at 20-30°C. Charged DM water (960.0 ml) to the wet material and heated the mass to 70-75°C followed by stirring for 55-65 minutes. Cooled the mass at 40-45°C. Filtered the mass at 40-45°C and washed with DM Water (120.0 ml) at 20-30°C. Suck dried well & unloaded the material. Dried the material for 15-20 hour in air tray dryer at 50-60°C (till water NMT 1.0%) to get desired compound.

EXAMPLE 3a: Synthesis of 4-(4-Chlorophenyl)-4-hydroxypiperidine:
Charge methanol (550.0 ml) and ethyl 4-(4-chlorophenyl)-4-hydroxypiperidne-1-carboxylate wet cake (110g) in RBF. Sodium hydroxide solution [155.3 g of NaOH dissolved in 220 mL of water] was added. Reaction mixture was heated to 75-80°C and stirred. After reaction completion, distil out methanol and DM Water (220 ml) was added and stirred the mass. Filtered the reaction mass & washed with Water. Again stirred wet material with water (440 ml) at 70-75°C, cooled and filtered at 40-45°C. Dried the material to get crude (70g). Charged crude material and toluene, heated to 60-65ºC, cooled and filtered. Dried in hot air tray dryer to give 4-(4-Chlorophenyl)-4-hydroxypiperidine (60g).

EXAMPLE 4: Synthesis of Haloperidol:
Charged toluene (2000.0 ml), 4-(4-Chlorophenyl)-4-hydroxypiperidine (200.0 g), sodium bicarbonate (396.8 g), potassium iodide (31.51 g) & 4-chloro-1-(4-fluorophenyl)butan-1-one (568.6 g) in 10.0 litre four neck round bottom flask fitted with dean stark at 20-25ºC. Heated the mass to 110-120°C and collected water azeotrope by upward displacement. Maintained the reaction mass at 110-120°C. After completion of reaction, cooled the reaction mass to 50-60°C. Distilled out toluene (up to 7V) at 50-60°C under vacuum at 50-60°C and left toluene (3V) in the reaction mass. Cooled the reaction mass to 40-45ºC. Charged ethyl acetate (1000.0 ml) and DM Water (2000.0 ml) in the reaction mass at 40-45°C. After charging heated the reaction mass to 70-80ºC. Stirred the reaction mass for 30 minute at 70-80°C till clear of solution. Separated the layers at 70-80°C. To the aqueous layer was added ethyl acetate (200.0 ml) at 40-45°C followed by heating at 70-80ºC. Separated the layers at 70-80°C. Concentrated the combined organic layer (up to 2V) under vacuum at 50-55°C and left mixture of ethyl acetate and toluene (7V) in the reaction mass. Cooled the mass to 20-25°C. Stirred the mass for 2-3 hour to 20-25°C. Filtered the mass and washed with ethyl acetate (100.0 ml) at 20-25°C. Suck dried to get crude compound.

1st Purification:
Charged ethyl acetate (1400.0 ml) to the crude material at 20-25ºC. Heated the mass till 75-80°C to obtain clear reaction mass. Stirred the mass for 25-35 minutes at 75-80°C. Gradually cooled the mass to 20-25ºC. Stirred the reaction mass for 2-3 hrs at 20-25ºC. Filtered the mass and washed with ethyl acetate (100.0 ml) at 20-25ºC. Suck dried to get pure Haloperidol.

2nd Purification:
Charged methanol (600.0 ml), acetone (600.0 ml) to the above obtained wet material in a round bottom flask at 20-25ºC. Stired the mass for 2-3 hour at 25-30°C. Filtered and washed with mixture of acetone (50.0 ml) and methanol (50.0 ml) at 25-30ºC. Suck dried to get pure Haloperidol.

3rd Purification:
Charged ethyl acetate (3000.0 ml) to the above obtained wet material in a round bottom flask at 20-25ºC. Heated the mass 75-80°C to get a clear solution. Cooled the solution to 20-25°C and stirred for 2-3 hours. Filtered and washed with ethyl acetate (100.0 ml). Dried at 40-50°C for 12-15 hours to final compound.

EXAMPLE 5: Synthesis of Haloperidol decanoate from Haloperidol
Charged dichloromethane (450.0 ml) and decanoic acid (68.75 g) in a round bottom flask at 20-25°C flushed with dichloromethane (40.0 ml). Stirred the reaction mass for 10-15 minutes [till solid gets dissolved] at 20-25ºC. Added oxalyl chloride (60.77 g) to the above reaction mass in 110-130 minutes at 20-25ºC and flushed with dichloromethane (10.0 ml). Stirred the mass for 55-65 minutes at 20-25ºC. Distilled out the dichloromethane and degassed the residue under vacuum for 30-60 minutes at 35-40ºC. Charged n-heptane (50.0 ml) to the above distilled mass and distilled out n-heptane under vacuum at 35-40ºC. Degassed the mass under vacuum for not less than 120 minutes at 35-40ºC to get decanoyl chloride. Meanwhile, charged dichloromethane (450.0 ml) in another two litre round bottom flask at 20-25ºC. Added Haloperidol (100.0 g) and triethylamine (32.24 g) into the above two litre round bottom flask and flushed with dichloromethane (50.0 ml) at 20-25ºC. Stirred the reaction mass for 10-15 minutes at 20-25ºC. Added decanoyl chloride slowly in the above reaction mass within 60-75 minutes at 20-25ºC. Stirred the mass at 20-25ºC till completion of reaction. After completion of reaction, added DM Water (500.0 ml) and stirred for 10-20 minutes at 20-25ºC. Separated the layers at 20-25ºC. To the organic layer was added 5% sodium bicarbonate solution at 20-25ºC. Stirred the reaction mass for 30 minutes, settled & separated the layers at 20-25ºC. Distilled out dichloromethane under vacuum for 30-60 minutes at 35-40ºC. Degassed the mass for 30-60 minutes at 35-40ºC. Cooled the above reaction mass to 20-25ºC. Charged n-heptane (500.0 ml) into the above mass (20-25ºC) and stirred it for 10-15 minutes at 20-25ºC. Added 5% Sodium bicarbonate solution [Sodium bicarbonate (25.0 g) in DM water (500.0 ml)] at 20-25ºC. Stirred the reaction mass for 30 minutes, settled & separated the layers at 20-25ºC. Charged organic layer and added 5% Sodium bicarbonate solution [Sodium bicarbonate (25.0 g) in DM water (500.0 ml)] at 20-25ºC. Stirred the reaction mass for 30 minutes, settled & separated the layers at 20-25ºC. Charged organic layer and added 5% sodium bicarbonate solution [Sodium bicarbonate (25.0 g) in DM water (500.0 ml)] at 20-25ºC. Stirred the reaction mass for 30 minutes, settled & separated the layers at 20-25ºC. Charged organic layer and added DM Water (500.0 ml) at 20-25ºC. Stirred the reaction mass for 30 minutes, settled & separated the layers at 20-25ºC. Charged organic layer &and added neutral activated Carbon (10.0 g) and stirred for 25-30 minutes at 20-25ºC. Filtered through Hyflo (10.0 g) and washed the bed with n-Heptane (50.0 ml). Cooled the mass -5 to 5ºC and seeded with Haloperidol decanoate (0.1g) at -5 to 5ºC. Stirred for 4-5 hour at -5 to 5ºC. Filtered at -5 to 5ºC. Washed with chilled n-Heptane (50.0 ml) at -5 to 5ºC. Again crystallised with n-heptane. Dried the material under vacuum for 20-25 hour at 20-25ºC to get final compound.
, Claims: WE CLAIM

1. A process for the preparation of Haloperidol or its pharmaceutically acceptable salt, wherein said process comprising the steps of:
a) converting compound of Formula IV to compound of Formula VI in presence of chloro bromo benzene of Formula V, magnesium source and haloalkane,
;
b) converting compound of Formula VI to 4-(4-chlorophenyl)-4-hydroxypiperidine of Formula III in presence of suitable base;
; and
c) converting compound of Formula III to Haloperidol or its pharmaceutically acceptable salt.

2. The process as claimed in claim 1, wherein said haloalkane used in step a) is selected from dibromoethane, 1-bromo-2-chloroethane, 1-bromo-3-chloro propane, bromoethane and mixture thereof.

3. The process as claimed in claim 1, wherein said suitable base used in step b) is selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium carbonate, cesium carbonate, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, calcium hydroxide and mixture thereof.
4. A process for the preparation of Haloperidol or its pharmaceutically acceptable salt, wherein said process comprising the steps of:
a) converting compound of Formula IV to compound of Formula VI in presence of chloro bromo benzene of Formula V, dibromoethane, magnesium source and suitable solvent,
;
b) converting compound of Formula VI to 4-(4-chlorophenyl)-4-hydroxypiperidine of Formula III in presence of sodium hydroxide and suitable solvent,
;
c) purifying compound of Formula III in suitable solvent; and
d) converting compound of Formula III or its acid addition salt to Haloperidol or its pharmaceutically acceptable salt.

5. The process as claimed in claim 4, wherein said suitable solvent is one or more solvents selected from protic and aprotic solvents such as group comprising of, but not limited to, alcohols such as methanol, ethanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, hexafluoroisopropyl alcohol, ethylene glycol, 1-propanol, 2-propanol (isopropyl alcohol), 2-methoxyethanol, 1-butanol, 2-butanol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, polyethylene glycol, 1-, 2-, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, phenol, glycerol; halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, trichloroethylene, perchloroethylene, 1,1,1-trichloroethane, 1,1,2-trichloroethane, chloroform, carbon tetrachloride; ethers such as diethyl ether, diisopropyl ether, methyl t-butyl ether, glyme, diglyme, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, dibutyl ether, dimethylfuran, 2-methoxyethanol, 2-ethoxyethanol, anisole; ketone solvents such as acetone, ethyl methyl ketone, diethyl ketone, methyl isobutyl ketone; esters solvents such as ethyl acetate, n-propyl acetate, n-butyl acetate, iso propyl acetate, isobutyl acetate, t-butyl acetate, ethyl formate, methyl acetate, methyl propanoate, ethyl propanoate, methyl butanoate, ethyl butanoate; hydrocarbon such as toluene, xylene, hexane, heptane, n-pentane, anisole, ethyl benzene, cyclohexane and the like; nitriles such as acetonitrile, propionitrile, butanenitrile; water; and mixtures thereof.

6. The process as claimed in claim 1 and 4, wherein said haloperidol is isolated as crystalline solid characterized by X-Ray powder diffraction pattern comprising peaks at about 6.52, and 19.57±0.2o?.

7. The process as claimed in claim 1 and 4, wherein said haloperidol pharmaceutically acceptable salt is haloperidol decanoate which is characterized by X-Ray powder diffraction pattern comprising peaks at about 5.1, 21.7 and 23.5 ±0.2o?.

8. The process as claimed in claim 7, wherein said crystalline haloperidol is prepared by a process comprising the steps of;
a) providing a solution of Haloperidol in ester solvent;
b) heating to solution between 65 oC-90oC;
c) isolating solid mass and optionally treating with one or more suitable solvent; and
b) isolating crystalline Haloperidol.

9. The process as claimed in claim 8, wherein said ester solvent is selected from ethyl acetate, propyl acetate, butyl acetate, propene acetate and mixture thereof.

10. A process for the preparation of crystalline form of Haloperidol, comprising the steps of;
a) providing a solution of Haloperidol in ethyl acetate;
b) heating to solution between 65 oC-90oC;
c) isolating solid mass and treating with mixture of acetone and methanol at ambient temperature;
d) isolating solid mass and dissolving in ethyl acetate at 65 oC-90oC; and
e) cooling and isolating crystalline Haloperidol.

Dated this, 26th day of Apr, 2022 For Mankind Pharma Ltd.

Dr. Anil Kumar
Chief Scientific Officer